History of the I4C
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I4C was established to obtain insights into the causes of childhood cancer using, for the first time, prospectively collected data and biospecimens from pregnancy.
A central premise was that reliable investigation of environmental and biological risk factors requires data collected prior to diagnosis. Achieving the necessary statistical power for such rare outcomes could only be realised by including very large numbers of participants. In practice, this required bringing together major birth and childhood cohorts internationally, creating a platform capable of addressing questions that no single study could answer.
Continue watching a video presentation and reading our history below:
A presentation on the history of I4C at the Annual Meeting in Korea in 2025, delivered by Terry Dwyer, a key initiator of the consortium.
Origins and Rationale
For decades, most knowledge about childhood cancer risk factors came from case–control studies. While valuable, these studies are subject to important limitations, including recall bias, selection bias, and the limited availability of pre-diagnostic biological samples. It was increasingly recognised that large prospective birth cohorts, collecting data and biospecimens from pregnancy onwards, offered a means of overcoming many of these challenges.
The concept of I4C emerged in 2004, when it became clear that only international collaboration could provide the scale needed to study childhood cancer.
The concept of I4C emerged during planning discussions for the U.S. National Children’s Study (NCS) in 2004. Terry Dwyer, Director of the Murdoch Children’s Research Institute in Melbourne, was asked by the Director of the National Children’s Study (NCS), Peter Scheidt, to examine the possibility of including children’s cancer in that large US cohort. His advice was that even very large individual cohorts - for example, the planned 100,000 participants in the NCS - would lack sufficient statistical power to investigate rare outcomes such as childhood cancer. However, by combining multiple cohorts internationally, each collecting detailed environmental, lifestyle, and biological data from pregnancy and early life, it would be possible to achieve the scale required to test key hypotheses arising from previous research. Martha Linet and Joe Fraumeni from NCI were approached and readily supported further development of the idea.
A defining feature of this approach was the use of prospectively collected data, enabling exposures to be measured before the onset of disease. This provides a more robust and less biased foundation for investigating aetiology, and allows the examination of critical windows of susceptibility during pregnancy and early childhood.
Formation of the Consortium
In 2005, representatives from 11 cohorts across four continents came together to establish I4C.
In 2005, an international workshop convened by the U.S. National Institutes of Health in Rockville, Maryland brought together representatives from 11 cohorts across four continents, along with experts in epidemiology, oncology, genetics, and environmental health. This meeting led to the formal establishment of the International Childhood Cancer Cohort Consortium (I4C).
A steering committee was formed, comprising investigators from participating cohorts as well as representatives from major research and funding organisations, including the National Institutes of Health and the U.S. Environmental Protection Agency. Early efforts focused on establishing governance structures, developing data-sharing agreements, and creating approaches to harmonise data across diverse cohorts.
The Murdoch Children’s Research Institute (MCRI) served as I4C’s coordinating institution from its establishment until 2024.
Development as a Research Platform
A defining feature of this approach was the use of prospectively collected data, enabling exposures to be measured before the onset of disease
Following its establishment, I4C evolved into a collaborative research platform pooling data from pregnancy and birth cohorts worldwide. Its central aim is to investigate the causes (aetiology) and underlying mechanisms of childhood cancers using prospectively collected exposure data and biological samples.
A key innovation of I4C has been to enable the harmonisation of data across cohorts, allowing pooled analyses while accounting for differences in study design and population characteristics. Supporting infrastructure has been established to facilitate this work, including:
- an International Data Coordinating Centre (IDCC) at MCRI to manage and harmonise data
- an International Biospecimen Coordinating Centre (IBCC) to support the sharing and analysis of biological samples was established in concept at IARC but has not yet been widely used. It may no longer be feasible among European members, given the decision under the GDPR.
Growth and expansion
Over time, I4C has expanded substantially. The initial six participating cohorts, whose recruitment spanned the 1950s through to the early 2000s, collectively contributed hundreds of thousands of mother–child pairs. Additional cohorts from a number of countries have since joined, or are preparing to contribute data, significantly increasing the scale and global reach of the consortium.
Over time, I4C has expanded substantially, increasing both the scale and the global reach of the consortium.
Drawing on rich birth cohort data spanning several decades, I4C has since 2025, expanded its scientific scope to include adolescent and young adult (AYA) cancers, as well as early-life and childhood cancers.
I4C has expanded also in its organizational structure and data governance. After the introduction of GDPR in Europe in 2018, I4C moved from individual-level data harmonisation to aggregated, federated analyses. Although a central IDCC is no longer in operation, the harmonisation developed through IDCC’s work remains a valuable foundation for future I4C work.
In 2024, responsibility for coordinating I4C was transferred to the Norwegian Institute of Public Health (NIPH). The consortium includes presently representatives from 12 cohorts.
Key Findings and Contributions
Early analyses have demonstrated the feasibility and value of combining harmonised data across cohorts to investigate childhood cancer risk factors, and over the period since its establishment, I4C has begun to generate important findings using pooled data from multiple prospective cohorts.
One of the first major findings examined the relationship between birthweight and childhood cancer risk, demonstrating a positive association between increasing birthweight and risk of both overall childhood cancer and childhood leukaemia. This work provided prospective evidence supporting observations from earlier case–control studies.
In addition to epidemiological analyses, I4C has contributed to methodological and laboratory advances, including the development of improved techniques for extracting and analysing DNA from neonatal dried blood spots, enabling epigenetic studies of early-life exposures.
More recent work has focused on identifying molecular and epigenetic markers associated with early-life exposures, with the aim of better understanding the biological mechanisms underlying childhood cancer. These efforts complement questionnaire-based analyses and represent an important step towards integrating epidemiological and molecular data within the consortium.
A full list of publications arising from I4C is available on the Norwegian Institute of Public Health website under Publications from I4C.
Ongoing Evolution
I4C continues to evolve as a global collaborative platform, bringing together epidemiological and molecular data to advance understanding of cancer aetiology
I4C continues to evolve as a global collaborative platform. Increasingly, it integrates epidemiological data with biological and molecular measures, including genetic, epigenetic, and other “omics” approaches, to better understand mechanisms underlying childhood cancer. Collaborations with other international consortia are further strengthening its ability to address complex research questions. By combining large-scale prospective data with interdisciplinary expertise, I4C is well positioned to advance understanding of cancer aetiology and to contribute to future prevention strategies.
The article is written by Terry Dwyer and Nicola Muizelaar.